Uncertainty of Estimates of Cancer Risks Derived by Extrapolation from High to Low Doses and from Animals to Humans

The uncertainties associated with extrapolating model-based cancer risks from high to low doses and animal-based cancer risks to humans are examined. It is argued that low-dose linear extrapolation based on statistical confidence limits calculated from animal data is designed to account for data uncertainty, model-selection uncertainty, and model-fitting instability. The intent is to err on the side of safety, that is, overstating rather than understating the true risk. The tendency toward conservatism in predicting human cancer risks from animal data based on linear extrapolation is confirmed by a real-data analysis of the various sources of uncertainty involved in extrapolating from animals to humans. Along with the tendency toward conservatism, a high degree of overall uncertainty in the interspecies extrapolation process is demonstrated. It is concluded that human cancer risk estimates based on animal data may underestimate the true risk by a factor of 10 or may overestimate that risk by a factor of 1,000.

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